Retinoic acid receptor alpha drives cell cycle progression and is associated with increased sensitivity to retinoids in T-cell lymphoma.

Xueju Wang,Konstantinos N Lazaridis,Surendra Dasari,Andrew L Feldman,Marshall E Kadin,Eric D Wieben,Rebecca L Boddicker,Grzegorz S Nowakowski

doi:10.18632/oncotarget.15441

Xueju Wang, Konstantinos N Lazaridis + Show 6 more

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https://doi.org/10.18632/oncotarget.15441

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Abstract

Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas with generally poor outcomes following standard therapy. Few candidate therapeutic targets have been identified to date. Retinoic acid receptor alpha (RARA) is a transcription factor that modulates cell growth and differentiation in response to retinoids. While retinoids have been used to treat some cutaneous T-cell lymphomas (CTCLs), their mechanism of action and the role of RARA in CTCL and other mature T-cell lymphomas remain poorly understood. After identifying a PTCL with a RARAR394Q mutation, we sought to characterize the role of RARA in T-cell lymphoma cells. Overexpressing wild-type RARA or RARAR394Q significantly increased cell growth in RARAlow cell lines, while RARA knockdown induced G1 arrest and decreased expression of cyclin-dependent kinases CDK2/4/6 in RARAhigh cells. The retinoids, AM80 (tamibarotene) and all-trans retinoic acid, caused dose-dependent growth inhibition, G1 arrest, and CDK2/4/6 down-regulation. Genes down-regulated in transcriptome data were enriched for cell cycle and G1-S transition. Finally, RARA overexpression augmented chemosensitivity to retinoids. In conclusion, RARA drives cyclin-dependent kinase expression, G1-S transition, and cell growth in T-cell lymphoma. Synthetic retinoids inhibit these functions in a dose-dependent fashion and are most effective in cells with high RARA expression, indicating RARA may represent a therapeutic target in some PTCLs.

Highlights

Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas of mature T-cell origin that demonstrate marked clinical, pathological, and molecular heterogeneity, with over 20 subtypes currently recognized by the World Health Organization [1]
Following identification of a RARAR394Q mutation in a PTCL patient being evaluated in an individualized medicine clinic, we demonstrated that both RARAR394Q and RARAwt accelerated growth of T-cell lymphoma cells, with modestly enhanced function of the mutant compared to the wild-type form
We demonstrated that the growth induction caused by Retinoic acid receptor alpha (RARA) was due to promotion of the cell cycle, G1-S transition

Summary

Introduction

Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas of mature T-cell origin that demonstrate marked clinical, pathological, and molecular heterogeneity, with over 20 subtypes currently recognized by the World Health Organization [1]. Outcomes generally are poor following standard combination chemotherapy regimens, most commonly cyclophosphamide, doxorubicin (hydroxydaunorubicin), Oncovin (vincristine), and prednisone (CHOP) [2]. These data indicate a pressing need for new therapeutic approaches in PTCL, attempts to improve outcomes using alternative chemotherapy regimens have been disappointing. Retinoic acid receptor alpha (RARA) is a transcription factor that forms heterodimers with retinoid X receptor (RXR) [4] These heterodimers bind to DNA motifs known as retinoic acid response elements (RAREs) and regulate gene transcription upon interaction with the natural ligand, retinoic acid, resulting in the regulation of genes involved in cellular growth and differentiation. Retinoic acid has demonstrated anti-proliferative effects in many tumor models, and as such, retinoic acid receptors (RARs) have been targeted therapeutically through the use of natural and synthetic retinoids

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